Cairo made his major league debut with the Toronto Blue Jays on April 17, 1996 as the starting 2nd baseman. In his first Major League at-bat, he hit a double off of Chuck Finley of the California Angels. He played in 9 games for the Blue Jays, with 6 hits in 27 at-bats for a .222 average. He also played in 120 games for the AAA Syracuse Chiefs, hitting .277.

On November 20, 1996, he was traded to the Chicago Cubs in exchange for minor leaguer Jason Stevenson. Cairo spent most of the 1997 season with the AAA Iowa Cubs, where he hit .279 in 135 games and was selected to the American Association All-Star team. He also appeared in 16 games for the Cubs and had 7 hits in 29 at-bats (.241).

In August 2001, the St. Louis Cardinals claimed Cairo on waivers from the Cubs. He remained with the Cardinals through the 2003 season. He hit .333 in 27 games in 2001, .250 in 108 games in 2002 and .245 in 92 games in 2003. He also appeared in the post-season for the first time in his career in 2001. In the 2002 National League Championship Series against the San Francisco Giants he had 5 hits, including a home run, in 13 at-bats.

In 2004, Cairo won the second base job with the Yankees after starting the year in a platoon with Enrique Wilson. Cairo led the league in percentage of productive outs in 2005 for players with a minimum of 40 at-bats. Cairo recorded 17 productive outs in 32 productive out situations, for a PO% of 0.531. Cairo had the highest winning percentage of team wins when he played in a game of any player in the majors in 2005 (for players with over 100 games played). However, the Yankees declined to offer him a contract for 2005 and signed Tony Womack as their new second baseman.

He was released on August 15. On August 19, 2007, the St. Louis Cardinals signed Cairo to a minor league contract, with him reporting to Triple-A Memphis on August 22. On September 1, 2007, the Cardinals activated him and brought him up to start at second base in a game against the Cincinnati Reds. He became a free agent after the season.

On July 10, the Mariners released Sexson and Cairo assumed the role of full-time first baseman for a few days until Bryan LaHair was finished ailing a sore toe. For the rest of the season, Cairo shared duties at first base with left-handed hitting LaHair, and started at the other infield positions when the incumbents had an off day.

On February 15, 2009, Cairo signed a minor league contract with an invitation to spring training with the Philadelphia Phillies.[1] On May 19, 2009, the Phillies outrighted Cairo to the AAA Lehigh Valley Iron Pigs.[2]

Cairo was sent back up to the Phillies on August 23 after they placed Greg Dobbs on the 15-day DL. He returned to the utility infield position, and was retained by the club through the remainder of the regular season. His performance during this stint, including several key hits, led to his inclusion in the division-winning team's post-season roster.[3]

On January 27, 2010, Cairo signed a minor league contract with the Cincinnati Reds. On April 2, Cairo made the Opening Day roster. On December 8, as a free agent, he signed a two-year deal with the Reds, which was the first multi-year contract of his career. He had the first multi-home run game of his career on August 13, against the San Diego Padres, in a game that the Reds won 13–1.

On February 14, 2013, the Reds announced that Cairo would operate as a special assistant to General Manager Walt Jocketty, effectively ending his playing career.[6] At the end of spring training the Reds third base coach Mark Berry was diagnosed with throat cancer, then Cairo filled as the team's bench coach while Chris Speier moved to third base.[7] With Berry's return Cairo moved back to his intended spot as assistant to Jocketty.